Progressive chronic kidney disease (CKD) particularly that due to diabetes, is a global problem that causes untold suffering in Veterans and the general population. Diabetic patients are at high risk of CKD and many face the prospect of irrevocable renal decline to end stage renal disease (ESRD). For some, renal transplantation is an effective way to treat ESRD, however, only a small minority receives a kidney. The majority of ESRD patients remain on dialysis, and most patients ultimately succumb to painful complications. One promising approach to CKD-ESRD is regenerative nephrology, and attempts have been made to restore renal function in animal models with stem cells. However, transplantation of stem cells from diverse sources has not yet fulfilled the basic postulates of cytotherapy: engraftment, differentiation and expansion. We devised a completely different strategy for renal regeneration by cell transplantation in CKD, and accomplished long-term kidney cell engraftment and successful renal regeneration with allogeneic transplants and autotransplants of adult primary kidney cells that express the tubulogenic protein Serum Amyloid A1 (SAA). This proposal aims to test the novel and clinically relevant hypothesis that transplantation with renal tubule cells expressing the tubulogenic protein serum amyloid A (SAA) rescues kidney function in experimental CKD. Furthermore, we propose that cells from kidneys with CKD can be expanded in vitro and then auto-transplanted to effect recovery of both renal structure and function non-invasively. These studies are a necessary prelude to future clinical translation in which part of one kidney would be removed, its tubules harvested and transfected and the derived tubular cells returned to the donor to restore renal function without need for immune suppression. The proposed work is derived from accumulated experience: First, we found that the acute phase protein SAA is critical in tubulogenesis in the embryo and during renal regeneration after ischemia (Kelly et al Am J Physiol 296: F1355, 2009). Second, immortalized renal tubule (NRK52E) cells reprogrammed with SAA and administered intravenously produce striking improvements in renal function in multiple models of acute kidney injury (Kelly et al Am J Physiol 299: F453, 2010). Third, transplantation with primary renal tubule cells resulted in significant recovery of structure and function in both chronic and acute kidney disease (Kelly et al Am J Physiol 303:F357, 2012). We already have conducted extensive experiments and found that CKD can be corrected in six rats with cells from a single donor of the same strain. Our hypothesis has generated the following specific aims: (1) To evaluate cytotherapy, including autotransplantation, as novel treatment for CKD in diabetic nephropathy and ischemia. (2) To determine the mechanisms by which cytotherapy with SAA expressing primary renal tubule cells restores renal function in CKD from diabetic nephropathy and ischemia. The proposed innovative, translational study will define mechanisms of renal regeneration, potentially extend the utility of organs available for transplantation, and develop means for autotransplantation. We suggest that further defining mechanisms of cytotherapy-mediated renal regeneration and improvement in kidney function, including cell grafting effects, will stimulate further research on regeneration and facilitate the development of therapies to target the specific mechanisms identified. The ultimate goal is the prevention and treatment of CKD in Veterans and the general population.